Method for producing 1,4-benzoxazine compound

ABSTRACT

The present invention provides an industrially advantageous method for producing a 1,4-benzoxazine compound useful as a medicine while avoiding safety and health risks. Specifically, the present invention provides a method for producing a 1,4-benzoxazine compound [A], which comprises the three steps in the following scheme, namely, a step of converting the amino group at 7-position in a compound [a] into a dimesylamino group, a step of coupling a compound [b] with a boronic acid compound, and a step of converting the 7-position in a compound [c] into a monomesylamino group. 
     
       
         
         
             
             
         
       
     
     In the above scheme, Ms is a methanesulfonyl group, and each of R′ and R″ is a hydrogen atom etc.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of copending application Ser. No.14/420,276, filed on Feb. 6, 2015, which was filed as PCT InternationalApplication No. PCT/JP2013/071446 on Aug. 8, 2013, which claims thebenefit under 35 U.S.C. §119(a) to Patent Application No. 2013-007041,filed in Japan on Jan. 18, 2013, and Patent Application No. 2012-176217,filed in Japan on Aug. 8, 2012 all of which are hereby expresslyincorporated by reference into the present application.

TECHNICAL FIELD

The present invention relates to a novel method for producing a1,4-benzoxazine compound which has an aldosterone receptor antagonisticaction, and is useful as a medicine such as an antihypertensive or adiuretic.

BACKGROUND ART

The recent research on aldosterone has revealed that said hormone isproduced not only by adrenal gland but also by other various organs suchas heart, blood vessel or brain, and that its receptor is also widelydistributed not only in cardiovascular tissue but also in other tissues.Further, aldosterone has been recognized not only as an exacerbationfactor of hypertension, but also as a risk hormone which has variousinjurious actions on cardiovascular tissue. Under these circumstances,an aldosterone receptor antagonist has been found to have features suchas a positive action on serious heart failure or acute myocardialinfarction in a recent large clinical trial, and thus is expected to bea potential drug useful for establishing an effective therapy forcardiovascular diseases.

Patent Literature 1 discloses a compound of the following generalformula [I]:

useful as an aldosterone antagonist. Among the compound [I] disclosed insaid Patent Literature 1, for example, a compound of the followingformula [A]:

namely,N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide,is expected to be clinically used as an aldosterone receptor antagonist.

As a method for producing the above compound [A], Patent Literature 1discloses the following synthetic method.

However, the final intermediate (2) in the above method has beenconfirmed to have a strong mutagenicity by the AMES test, and thus has aproblem of carrying safety and health risks when used as a syntheticintermediate of a medicine. Therefore, as a synthetic method forproducing the compound [A], it has been desired to establish anindustrially advantageous method without carrying the above safety andhealth risks.

Also, in general, regarding a compound which is expected to be useful asa medicine, it is known that its physical properties (e.g., the presenceor absence of an amorphous state, a crystal and a polymorph thereof,etc.) significantly affect the purity or stability (e.g., photostabilityand humidity stability, etc.) as an active pharmaceutical ingredient,the stability in a formulation, and the bioavailability when used as amedicine. Therefore, it is an important problem in the development of amedicine to obtain stably and on an industrial scale a single crystal ofa medicinal compound having the above excellent physical properties.However, it is difficult to reasonably predict the presence or absenceof a crystal and a polymorph thereof of a certain compound. Meanwhile,Patent Literature 1 discloses that the compound [A] was obtained as apowder material.

BACKGROUND ART DOCUMENTS Patent Literatures

Patent Literature 1: WO2007/089034

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention provides a novel method for industriallyadvantageously producing the above compound [A] useful as a medicine.Furthermore, the present invention relates to novel crystal forms of thecompound [A] which is preferable as a medicinal compound.

Means for Solving the Problems

The present inventors have carried out intensive studies for solving theabove problems, and as a result, found that a synthetic methodcomprising the step in the following formula (i.e., a step of reacting acompound [b] with a boronic acid compound [d] to produce a compound [c])can produce the target compound [A] in a high yield while avoidingsafety and health risks (e.g., risks associated with the mutagenicity ofthe synthetic intermediates), and finally completed the presentinvention. Meanwhile, to the best of the applicant's knowledge, thefollowing compound [b] and the compound [c] are novel compounds.

In the above scheme, Ms is a methanesulfonyl group, and R and R′ are thesame or different and each of them is a hydrogen atom or an alkyl group,or both of them combine together to form an alkylene group.

In addition to the above method, the present inventors have found thatthe compound [A] (a powder material) disclosed in Patent Literature 1 ispresent in a specific crystal form (Form D crystal), and further foundthat the compound [A] has multiple crystal forms (crystal polymorphs)different from the Form D crystal, said novel crystals have higherstability as compared to the Form D crystal, and also have desiredprofiles as a medicinal compound (i.e., an active pharmaceuticalingredient), and finally completed the present invention.

Namely, the present invention relates to:

[1] a method for producing a 1,4-benzoxazine compound of the followingformula [A]:

which comprises the following steps of:

(step a) reacting a compound of the following formula [a]:

with methanesulfonyl halide in the presence of a base to produce acompound of the following formula [b]:

wherein Ms is a methanesulfonyl group,

(step b) reacting said compound [b] with a boronic acid compound of thefollowing formula [d]:

wherein R and R′ are the same or different and each of them is ahydrogen atom or an alkyl group, or both of them combine together toform an alkylene group,

-   or an equivalent thereof, in the presence of a copper catalyst, in    the presence or absence of a base, and in the presence or absence of    a ligand to produce a compound of the following formula [c]:

wherein the symbol is the same as defined above,

-   and

(step c) converting the substituent at 7-position (dimesylamino group)in said compound [c] into a monomesylamino group to produce the compoundof the above formula [A];

[2] the method according to the above item [1], wherein themethanesulfonyl halide is methanesulfonyl chloride;

[3] the method according to the above item [1], wherein the compound [d]is a compound of the following formula:

or an equivalent thereof;

[4] the method according to the above item [1], [2] or [3],characterized in that

(1) the step a is carried out in a solvent selected from the groupconsisting of acetonitrile, methyl ethyl ketone, ethyl acetate,tetrahydrofuran and acetone, and in the presence of a base selected fromtriethylamine, tetramethylethylenediamine and1,8-diazabicyclo[5.4.0]undec-7-ene,

(2) the step b is carried out in a solvent selected fromdimethylsulfoxide and N,N-dimethylacetamide, in the presence of a coppercatalyst selected from the group consisting of copper acetate, copperhalide, copper nitrate and a copper salt of trifluoromethanesulfonicacid, in the presence or absence of one or more bases selected fromtriethylamine, diisopropylethylamine, tributylamine, tripropylamine,trioctylamine, dimethylbenzylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,N-ethylmorpholine, N-methylmorpholine, sodium hydrogen carbonate and anaqueous ammonia, in the presence or absence of one or more ligandsselected from dimethylaminopyridine, 2-aminopyridine, 4-methylpyridine,2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine, N-methylimidazole,N-butylimidazole and pyrazine, and under oxygen supply to the reactionsystem, and

(3) the step c is carried out in a solvent selected from ethanol,isopropanol, n-propanol, acetone, methyl ethyl ketone anddimethylsulfoxide or a mixture of said solvent and water, and in thepresence of a base selected from potassium carbonate and sodiumhydroxide;

[5] a method for producing a compound of the following formula [A]:

which comprises the step of converting the substituent at 7-position(dimesylamino group) in a compound of the following formula [c]:

wherein Ms is a methanesulfonyl group,

-   into a monomesylamino group;

[6] the method according to the above item [5], characterized in thatthe conversion of the substituent at 7-position (dimesylamino group)into the monomesylamino group is carried out in a solvent selected fromethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone anddimethylsulfoxide or a mixture of said solvent and water, and in thepresence of a base selected from potassium carbonate and sodiumhydroxide;

[7] a method for producing a compound of the following formula [c]:

wherein Ms is a methanesulfonyl group,

-   which comprises the following steps of:

(step a) reacting a compound of the following formula [a]:

with methanesulfonyl halide in the presence of a base to produce acompound of the following formula [b]:

wherein the symbol is the same as defined above,

-   and (step b) reacting said compound [b] with a boronic acid compound    of the following formula [d]:

wherein R and R′ are the same or different and each of them is ahydrogen atom or an alkyl group, or both of them combine together toform an alkylene group,

-   or an equivalent thereof, in the presence of a copper catalyst, in    the presence or absence of a base, and in the presence or absence of    a ligand;

[8] the method according to the above item [7], characterized in that

(1) the step a is carried out in a solvent selected from the groupconsisting of acetonitrile, methyl ethyl ketone, ethyl acetate,tetrahydrofuran and acetone, and in the presence of a base selected fromtriethylamine, tetramethylethylenediamine and1,8-diazabicyclo[5.4.0]undec-7-ene, and

(2) the step b is carried out in a solvent selected fromdimethylsulfoxide and N,N-dimethylacetamide, in the presence of a coppercatalyst selected from the group consisting of copper acetate, copperhalide, copper nitrate and a copper salt of trifluoromethanesulfonicacid, in the presence or absence of one or more bases selected fromtriethylamine, diisopropylethylamine, tributylamine, tripropylamine,trioctylamine, dimethylbenzylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,N-ethylmorpholine, N-methylmorpholine, sodium hydrogen carbonate and anaqueous ammonia, in the presence or absence of one or more ligandsselected from dimethylaminopyridine, 2-aminopyridine, 4-methylpyridine,2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine, N-methylimidazole,N-butylimidazole and pyrazine, and under oxygen supply to the reactionsystem;

[9] a method for producing a compound of the following formula [c]:

wherein Ms is a methanesulfonyl group,

-   which comprises the step of reacting a compound of the following    formula [b]:

wherein the symbol is the same as defined above,

-   with a boronic acid compound of the following formula [d]:

wherein R and R′ are the same or different and each of them is ahydrogen atom or an alkyl group, or both of them combine together toform an alkylene group,

-   or an equivalent thereof, in the presence of a copper catalyst, in    the presence or absence of a base, and in the presence or absence of    a ligand;

[10] the method according to the above item [9], characterized in thatthe coupling reaction of the compound [b] with the compound [d] iscarried out in a solvent selected from dimethylsulfoxide andN,N-dimethylacetamide, in the presence of a copper catalyst selectedfrom the group consisting of copper acetate, copper halide, coppernitrate and a copper salt of trifluoromethanesulfonic acid, in thepresence or absence of one or more bases selected from triethylamine,diisopropylethylamine, tributylamine, tripropylamine, trioctylamine,dimethylbenzylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,N-ethylmorpholine, N-methylmorpholine, sodium hydrogen carbonate and anaqueous ammonia, in the presence or absence of one or more ligandsselected from dimethylaminopyridine, 2-aminopyridine, 4-methylpyridine,2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine, N-methylimidazole,N-butylimidazole and pyrazine, and under oxygen supply to the reactionsystem;

[11] a compound of the following formula [b]:

wherein Ms is a methanesulfonyl group;

-   and

[12] a compound of the following formula [c]:

wherein Ms is a methanesulfonyl group.

Further, the present invention relates to:

[13] a crystal (Form A crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide,which has at least one diffraction peak at 6.7° to 11.0°, and hasdiffraction peaks at 18.1° and 23.7° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction;

[14] the crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to the above item [13], which has an additional diffractionpeak at 10.2° as the diffraction angle (2θ±0.2°);

[15] a crystal (Form B crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide,which has at least one diffraction peak at 6.7° to 11.0°, and hasdiffraction peaks at 14.8° and 18.3° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction;

[16] the crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to the above item [15], which has additional diffraction peaksat 10.8° and 23.2° as the diffraction angle (2θ±0.2°);

[17] a crystal (Form C crystal) of a dimethylsulfoxide monosolvate ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide, which hasdiffraction peaks at 19.3° and 29.6° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction;

[18] the crystal of the dimethylsulfoxide monosolvate ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to the above item [17], which has an additional diffractionpeak at 11.3° as the diffraction angle (2θ±0.2°);

[19] a pharmaceutical composition comprising the crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide or adimethylsulfoxide monosolvate thereof according to any one of the aboveitems [13] to [18] and a pharmacologically acceptable carrier;

[20] the pharmaceutical composition according to the above item [19],which is a preventive or therapeutic agent for various diseases ordisease states caused by enhanced MR activity and/or elevatedaldosterone level;

[21] the pharmaceutical composition according to the above item [19],which is a preventive or therapeutic agent for hypertension, heartfailure, myocardial infarction, angina, cardiac hypertrophy,myocarditis, myocardial/vascular fibrosis, baroreceptor dysfunction,volume overload or arrhythmia;

[22] the pharmaceutical composition according to the above item [19],which is a preventive or therapeutic agent for primary/secondaryaldosteronism, Addison's disease, Cushing's syndrome or Bartter'ssyndrome;

[23] the pharmaceutical composition according to the above item [19],which is a preventive or therapeutic agent for a renal disease;

[24] the pharmaceutical composition according to the above item [23],wherein the renal disease is diabetic nephropathy;

[25] a method for producing a Form A crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving at least one diffraction peak at 6.7° to 11.0°, and havingdiffraction peaks at 18.1° and 23.7° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction, which comprises the step of heating acrystal (Form D crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving no diffraction peak at 6.7° to 11.0°, but having diffractionpeaks at 6.0°, 11.9°, 17.0°, 17.6° and 19.0° as the diffraction angle(2θ±0.2°), or a crystal (Form B crystal) ofN-[4(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving at least one diffraction peak at 6.7° to 11.0°, and havingdiffraction peaks at 14.8° and 18.3° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction in a liquid medium or in the absence ofa medium; and

[26] the method for producing the Form A crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to the above item [25], characterized by heating the Form Bcrystal in ethanol as the liquid medium at 75° C. to 85° C.

Effects of the Invention

By using the method of the present invention, the 1,4-benzoxazinecompound [A] useful as a medicine can be prepared in a high yield. Also,the method of the present invention can use an intermediate having lowersafety and health risks (e.g., mutagenicity etc.), and thus can be anindustrially advantageous method.

The novel crystals of the present invention (Form A crystal, Form Bcrystal and Form C crystal) are highly stable. Especially, the Form Acrystal does not transform to an amorphous state or other crystal formby a factor such as heating and is non-hygroscopic, and thus haspreferable features as a crystal form of a medicinal compound. Further,the Form A crystal is also characterized in that it is highly stable ina formulation, and thus is a preferable crystal form as an activepharmaceutical ingredient.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern of the Form A crystalof the compound [A].

FIG. 2 shows the X-ray powder diffraction pattern of the Form B crystalof the compound [A].

FIG. 3 shows the X-ray powder diffraction pattern of the Form C crystalof the compound [A].

FIG. 4 shows the X-ray powder diffraction pattern of the Form D crystalof the compound [A].

EMBODIMENTS TO CARRY OUT THE INVENTION

(Step a)

The reaction of the compound [a] with methanesulfonyl halide can becarried out in a solvent, and in the presence of a base. As themethanesulfonyl halide, methanesulfonyl chloride is preferable. Thesolvent may be any solvent as long as it does not disturb the presentreaction, and examples of the solvent include an aromatic hydrocarbonsuch as toluene, an amide such as N,N-dimethylacetamide, a nitrile suchas acetonitrile, a ketone such as acetone or methyl ethyl ketone, anester such as ethyl acetate, an ether such as tetrahydrofuran, and thelike. Among them, acetonitrile, methyl ethyl ketone, ethyl acetate,tetrahydrofuran and acetone are preferable, and acetonitrile is morepreferable. Examples of the base include a tertiary amine such astriethylamine, diisopropylethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), an alkylenediamine such astetramethylethylenediamine (TMEDA), Proton Sponge (registeredtrademark), and the like, and among them, triethylamine,tetramethylethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene arepreferable, and triethylamine is more preferable. Amount of themethanesulfonyl halide to be used is 1.0 to 5.0 molar equivalent,preferably 2.0 to 3.0 molar equivalent to the compound [a]. Amount ofthe base to be used is 1.0 to 5.0 molar equivalent, preferably 2.0 to3.0 molar equivalent to the compound [a]. The methanesulfonyl halide andthe base may be added to the reaction system in two or three portionsdepending on the reaction progress. Amount of the solvent to be used is10 to 20 V/W, preferably 10 to 15 V/W to the compound [a]. The presentreaction can be carried out at 0 to 50° C., preferably 30 to 50° C. Thereaction product, i.e., the compound [b], can be obtained in a highpurity by adding water to the reaction mixture, followed by carrying outa solid-liquid separation.

(Step b)

The reaction (coupling) of the compound [b] with the boronic acidcompound [d] can be carried out in a solvent, in the presence of acopper catalyst, in the presence or absence of a base, and in thepresence or absence of a ligand. The solvent may be any solvent as longas it does not disturb the present reaction, and examples of the solventinclude an ether such as tetrahydrofuran, a ketone such as acetone ormethyl ethyl ketone, an amide such as N,N-dimethylacetamide, a nitrilesuch as acetonitrile, dimethylsulfoxide, and the like. Among them,dimethylsulfoxide and N,N-dimethylacetamide are preferable, anddimethylsulfoxide is more preferable. Examples of the copper catalystinclude a copper compound such as a copper acetate (copper(I) acetate orcopper(II) acetate), a copper halide (copper chloride, copper bromide,copper iodide, etc.), copper sulfate, copper nitrate, copper(II) oxide,copper, copper-carbon or a copper salt of trifluoromethanesulfonic acid(Cu(OTf)₂ trihydrate), and among them, copper acetate, copper halide,copper nitrate and a copper salt of trifluoromethanesulfonic acid arepreferable, and copper(II) acetate is more preferable. Said copper(II)acetate may be used in the form of a hydrate. Examples of the baseinclude a tertiary amine such as triethylamine, diisopropylethylamine,tributylamine, tripropylamine, trioctylamine, dimethylbenzylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, N-ethylmorpholine orN-methylmorpholine, a pyridine such as pyridine ordimethylaminopyridine, an alkali metal base such as sodium hydrogencarbonate or sodium acetate, tetramethylethylenediamine,1,4-diazabicyclo[2.2.2]octane (DABCO), ammonium acetate, an aqueousammonia, a mixture thereof, and the like, and among them, triethylamine,diisopropylethylamine, tributylamine, tripropylamine, trioctylamine,dimethylbenzylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,N-ethylmorpholine, N-methylmorpholine, sodium hydrogen carbonate, anaqueous ammonia and a mixture thereof are preferable, and triethylamine,tributylamine, and a mixture thereof are more preferable. Examples ofthe ligand include a pyridine such as dimethylaminopyridine (DMAP),2-aminopyridine, 4-methylpyridine (4-picoline), 2,6-dimethylpyridine(2,6-lutidine), 3,5-dimethylpyridine (3,5-lutidine),2,4,6-trimethylpyridine (2,4,6-collidine) or pyridine, an imidazole suchas 1,2-dimethylimidazole, N-methylimidazole (NMI) or N-butylimidazole,1,4-diazabicyclo[2.2.2]octane (DABCO), pyrazine, a mixture thereof, andthe like, and among them, dimethylaminopyridine, 2-aminopyridine,4-methylpyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine,N-methylimidazole, N-butylimidazole and pyrazine are preferable,dimethylaminopyridine, N-methylimidazole, 4-methylpyridine,N-butylimidazole and pyridine are more preferable, and N-methylimidazoleand 4-methylpyridine are particularly preferable. Amount of the boronicacid compound [d] to be used is 1.0 to 3.0 molar equivalent, preferably1.0 to 2.0 molar equivalent to the compound [b]. Examples of theequivalent of the boronic acid compound [d] and [d-1] include a boroxinecompound of the following formula:

and the amount to be used is 0.7 to 1.7 molar equivalent, preferably 0.7to 1.5 molar equivalent to the compound [b]. Amount of the coppercatalyst to be used is 0.01 to 1.5 molar equivalent, preferably 0.1 to1.0 molar equivalent in terms of copper amount to the compound [b]. Whenthe base is used, the amount to be used is 0.4 to 3.0 molar equivalent,preferably 0.8 to 2.0 molar equivalent to the compound [b]. When theligand is used, the amount to be used is 0.01 to 1.0 molar equivalent,preferably 0.1 to 0.5 molar equivalent to the compound [b]. Amount ofthe solvent to be used is 5 to 20 V/W, preferably 5 to 15 V/W to thecompound [b]. The present reaction can be carried out at 15 to 60° C.,preferably 15 to 30° C.

The present reaction is preferably carried out under oxygen supply(e.g., air induction etc.) to the reaction system.

The separation of the compound [c] from the above reaction mixture canbe carried out by a conventional solid-liquid separation method. Forexample, the compound [c] can be obtained as a crystal by (1) addingmethanol and an acid (e.g., aqueous hydrochloric acid solution etc.) tothe reaction mixture, followed by collecting the precipitated crystals,then washing them with water and methanol etc. and drying them, or (2)adding dropwise the reaction mixture to a mixed solution ofdimethylsulfoxide/water/an acid (e.g., aqueous hydrochloric acidsolution etc.), followed by collecting the precipitated crystals, thenwashing them successively with a mixed solution ofdimethylsulfoxide/water and water, and drying them.

The compound [c] is also characterized in that it is easilycrystallized, and stable to the environmental factors (e.g., acid andtemperature) in crystallization. Also, the compound [c] has lowermutagenicity, and thus is preferable as a synthetic intermediate of amedicinal compound.

(Step c)

The conversion of the substituent at 7-position (dimesylamino group) inthe compound [c] into the monomesylamino group can be carried out bytreating said compound [c] with a base in a solvent. The solvent may beany solvent as long as it does not disturb the present reaction, andexamples of the solvent include an alcohol such as ethanol, n-propanolor isopropanol, a ketone such as acetone or methyl ethyl ketone, anether such as tetrahydrofuran, dimethylsulfoxide, a mixed solvent of oneor more of these organic solvents and water, and the like. Among them,ethanol, n-propanol, isopropanol, acetone, methyl ethyl ketone,dimethylsulfoxide, and a mixed solvent of one or more of these organicsolvents and water are preferable. Examples of the base include analkali metal carbonate such as potassium carbonate or sodium carbonate,an alkali metal hydroxide such as sodium hydroxide, potassium hydroxideor lithium hydroxide, potassium phosphate, tetrabutylammonium fluoride,and the like, and among them, potassium carbonate and sodium hydroxideare preferable. Amount of the base to be used is 1.0 to 5.0 molarequivalent, preferably 1.5 to 3.0 molar equivalent to the compound [c].Amount of the solvent to be used is 5 to 20 V/W, preferably 5 to 10 V/Wto the compound [c]. The present reaction can be carried out at 15 to50° C., preferably 20 to 30° C.

The compound [A] can be separated from the above reaction mixture by aconventional solid-liquid separation method. For example, the compound[A] can be obtained as crystals by adding an acid (e.g., aqueoushydrochloric acid solution etc.) to the reaction mixture forneutralization, followed by collecting the precipitated crystals, thenwashing them with water and drying them. If necessary, the reactionmixture may be treated with activated carbon for the purpose of removalof by-products, decolorization, or the like.

The compound [A] in a desired crystal form can be obtained byappropriately selecting the solvent used in the above (step c) reaction.For example, when a ketone such as acetone or methyl ethyl ketone,dimethylsulfoxide or a mixed solvent of one or more of these organicsolvents and water is used as the reaction solvent, the target compound[A] can be obtained mainly as the Form A crystal. When a mixed solventof an organic solvent and water is used, the mixture ratio of water(V/V) is about 5% to about 50%, preferably about 30% to about 40%.

When an alcohol such as ethanol, n-propanol or isopropanol,dimethylsulfoxide, or a mixed solvent of one or more of these organicsolvents and water is used as the reaction solvent, the target compound[A] can be obtained mainly as the Form B crystal or the Form D crystal.

Furthermore, the present inventors have confirmed by an experiment forscreening crystal forms that the compound [A] can be present as the FormC crystal (a dimethylsulfoxide monosolvate). The Form C crystal of thecompound [A] can be obtained by preparing a solution of said compound indimethylsulfoxide, allowing said solution to stand for a certain periodof time, then collecting the precipitated crystals by filtration, anddrying them.

When the compound [A] obtained by the above method of the presentinvention is present as the Form B or Form D crystal, the Form A crystalof the compound [A] can be obtained, for example, by heating underreflux (75° C. to 85° C.) a suspension of said Form B or Form D crystalin ethanol for 2 to 15 hours, then cooling it, and collecting thecrystals. Meanwhile, when the compound [A] obtained by the above methodof the present invention is present as the Form C crystal, the Form Bcrystal can be obtained by suspending said Form C crystal in water,stirring it, and then collecting the crystals.

Furthermore, the Form A crystal can also be obtained by heating the FormB crystal or the Form D crystal at 160° C. to 230° C.

As mentioned above, it has been confirmed that the compound [A] has fourcrystal polymorphs. Among these four crystal polymorphs, the Form Acrystal, the Form B crystal and the Form C crystal are novel crystalforms.

Form A crystal of compound [A]:

The Form A crystal of the present invention is a crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide which hasat least one diffraction peak at 6.7° to 11.0°, and has diffractionpeaks at 18.1° and 23.7° as the diffraction angle (2θ±0.2°) in the X-raypowder diffraction (CuKα radiation). More specifically, said crystal isan anhydrous crystal having no adhesion water, and has diffraction peaksat 10.2°, 18.1°, 20.2° and 23.7° as the diffraction angle (2θ±0.2°) inthe above X-ray powder diffraction. Still more specifically, saidcrystal has diffraction peaks at 8.3°, 9.7°, 10.2°, 13.0°, 13.6°, 18.1°,20.2°, 22.4°, 23.7°, 25.1° and 25.7° as the diffraction angle (2θ±0.2°)in the above X-ray powder diffraction. Particularly specifically, saidForm A crystal has diffraction peaks in the diffraction angles (2θ)shown in Table 1 described below in the above X-ray powder diffraction.

Also, the Form A crystal of the present invention has an endothermicpeak at about 238° C. in the differential scanning calorimetry (DSC).

Form B crystal of compound [A]:

The Form B crystal of the present invention is a crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide which hasat least one diffraction peak at 6.7° to 11.0°, and has diffractionpeaks at 14.8° and 18.3° as the diffraction angle (2θ±0.2°) in the X-raypowder diffraction (CuKα radiation). More specifically, said crystal isan anhydrous crystal having no adhesion water, and has diffraction peaksat 10.8°, 14.8°, 18.3° and 23.2° as the diffraction angle (2θ±0.2°)inthe above X-ray powder diffraction. Still more specifically, saidcrystal has diffraction peaks at 7.5°, 10.2°, 10.8°, 14.8°, 15.9°,16.9°, 18.3°, 19.3°, 21.5°, 23.2°, 25.6° and 29.1° as the diffractionangle (2θ±0.2°) in the above X-ray powder diffraction. Particularlyspecifically, the Form B crystal of the present invention hasdiffraction peaks in the diffraction angles (2θ) shown in Table 2described below in the above X-ray powder diffraction.

Form C crystal of compound [A]:

The Form C crystal of the present invention is a crystal of adimethylsulfoxide monosolvate of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide which hasdiffraction peaks at 19.3° and 29.6° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction (CuKα radiation). More specifically,said crystal has diffraction peaks at 11.3°, 19.3° and 29.6° as thediffraction angle (2θ±0.2°)in the above X-ray powder diffraction. Stillmore specifically, said crystal has diffraction peaks at 11.3°, 13.0°,15.7°, 17.0°, 17.8°, 19.3°, 21.2°, 22.4°, 25.1°, 27.5° and 29.6° as thediffraction angle (2θ±0.2°) in the above X-ray powder diffraction.Particularly specifically, the Form C crystal of the present inventionhas diffraction peaks in the diffraction angles (2θ) shown in Table 3described below in the above X-ray powder diffraction.

The crystals of the present invention obtained by the above method havepreferable features as crystal forms of a medicinal compound. Forexample, the Form A crystal is characterized in that it has lowhygroscopicity, and hardly makes a transition to other crystal form byheating, and thus is particularly preferable as a crystal form of thecompound [A]. Furthermore, the Form A crystal is also characterized byits high stability in a formulation.

The Form B crystal is characterized in that it has low hygroscopicity,and higher thermostability as compared to the crystal (Form D crystal)of the compound [A] disclosed in Patent Literature 1, and thus is one ofthe preferable crystal forms of the compound [A]. Also, said Form Bcrystal can be converted into the Form A crystal by heating (75° C. to85° C.) in a liquid medium (e.g., an organic solvent such as ethanol),and thus is also useful as a precursor of the target substance (Form Acrystal) of the above method of the present invention.

While the Form C crystal is obtained as a dimethylsulfoxide monosolvate,said crystal can be easily converted into the Form B crystal by washingwith water and drying, and thus is useful as a precursor of the Form Bcrystal.

Meanwhile, as is clear from the X-ray powder diffraction pattern (CuKαradiation) (FIG. 4), the crystal (Form D crystal) of the compound [A](N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide) disclosedin Patent Literature 1 (Example 9) does not have a diffraction peak at6.7° to 11.0°, but has diffraction peaks at 6.0°, 11.9°, 17.0°, 17.6°and 19.0° as the diffraction angle (2θ±0.2°), and thus is clearlydifferent from the crystal forms of the present invention.

Said compound [A] (Form A crystal etc.) is useful in the prevention ortreatment of various diseases or disease states that involvemineralocorticoid receptor (MR) and/or aldosterone. Examples of suchdiseases include a cardiovascular disease or a blood-related diseasesuch as essential hypertension; secondary hypertension (renovascularhypertension, fluid retention type hypertension, etc.); pulmonaryhypertension; hypotension; abnormal circadian blood pressure; heartfailure (acute heart failure, chronic heart failure or congestive heartfailure); angina; myocardial infarction; cardiomyopathy; cardiachypertrophy; myocarditis; myocardial/vascular fibrosis; myocardialischemia; baroreceptor dysfunction; arrhythmia; tachycardia;cerebrovascular accident (CVA) and a sequel thereof; transient ischemicattack (TIA); cerebral stroke; cerebrovascular dementia; hypertensiveencephalopathy; cerebral infarction; cerebral edema; cerebrovasculardisorder; peripheral circulatory disturbance including Raynaud's diseaseand Buerger's disease; intermittent claudication; venous incompetency;arteriosclerosis (coronary arteriosclerosis, cerebral arteriosclerosis,peripheral arteriosclerosis, etc.); vascular hypertrophy; vascularhypertrophy/occlusion after intervention including percutaneoustransluminal coronary angioplasty (PTCA); vascularreocclusion/restenosis after bypass graft surgery (CABG etc.); rejectionafter organ transplant; thrombosis; deep vein thrombosis; occlusiveperipheral circulatory disturbance; arteriosclerosis obliterans;thromboangiitis obliterans; thrombocytopenia; polycythemia; multipleorgan failure; vascular endothelial dysfunction; renal diseases (renalfailure, nephritis, glomerulonephritis, IgA nephropathy, progressivenephropathy, glomerulosclerosis, diabetic nephropathy, thromboticmicroangiopathy, dialysis complication, irradiation-induced nephropathy,etc.); vascular purpura; autoimmune hemolytic anemia; disseminatedintravascular coagulation (DIC); or multiple myelosis. Particularly, thecompound [A] (Form A crystal etc.) is useful as a preventive ortherapeutic agent for (1) a cardiovascular disease such as hypertension,heart failure, myocardial infarction, angina, cardiac hypertrophy,myocarditis, myocardial/vascular fibrosis, baroreceptor dysfunction,volume overload or arrhythmia, (2) a disease such as primary/secondaryaldosteronism, Addison's disease, Cushing's syndrome or Bartter'ssyndrome, or (3) a renal disease such as diabetic nephropathy.

The compound [A] (Form A crystal, Form B crystal, etc.) can be orally orparenterally administered alone or as a pharmaceutical compositioncomprising the compound [A] and a pharmacologically acceptable carrier.Examples of the dosage form of such pharmaceutical composition include,but are not limited to, a conventional solid formulation or a liquidformulation such as a tablet, a granule, a capsule, a powder, aninjection, an inhalant or a suppository.

Examples of the pharmacologically acceptable carrier include anexcipient, a lubricant, a binder, a disintegrant, a water-solublepolymer, and the like in a solid formulation; and a solvent, asolubilizing agent, an isotonizing agent, a buffer, a suspending agent,and the like in a liquid formulation. Also, in addition to the abovecarrier, the pharmaceutical composition of the present invention maycontain a conventional pharmaceutical additive such as an antioxidant, apreservative, a sweetening agent, an acidulant, a colorant, or aflavoring agent, if necessary.

The dose of the crystal (compound [A]) of the present invention variesdepending on administration method, or age, weight, or condition ofpatient, and preferably 0.001 to 10 mg/kg, particularly 0.01 to 1 mg/kgper day in parenteral administration, and normally 0.01 to 100 mg/kg,particularly 0.1 to 10 mg/kg per day in oral administration.

The starting compound [a] in the present invention can be producedaccording to, for example, the method disclosed in Patent Literature 1(i.e., the following Reaction Scheme 1).

In the above scheme, R^(a) is an alkyl group, and W is a halogen atom.

Examples of the halogen atom (W) in the compound [f] include a chlorineatom and a bromine atom, and among them, a bromine atom is preferable.The reaction of the compound [e] with the compound [f] can be carriedout in an appropriate solvent (e.g., an ether such as dimethylsulfoxide,an amide such as dimethylformamide, or an ester such as ethyl acetate,etc.), in the presence of a base (e.g., an alkali metal carbonate suchas potassium carbonate, etc.), and at room temperature to elevatedtemperature, preferably 20 to 30° C.

The reduction of the compound [g] (i.e., reduction of the nitro group at7-position) can be carried out in an appropriate solvent (e.g., analcohol such as methanol or ethanol, etc.), in the presence of apalladium catalyst such as palladium carbon or palladium hydroxidecarbon, under hydrogen atmosphere (or in the presence of ammoniumformate), and at 10 to 70° C., preferably 20 to 30° C.

Throughout the present specification, alkyl means a linear or branchedC₁₋₆ alkyl group, preferably a linear or branched C₁₋₄ alkyl group, andalkylene means a linear or branched C₁₋₆ alkylene group, preferably alinear or branched C₂₋₆ alkylene group.

EXAMPLES Example 1 (1) Preparation ofN-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide

To a suspension of 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3-(4H)-one(150 g) in acetonitrile (1500 mL) was added dropwise triethylamine (79g) at 40° C., then to the mixture was added dropwise methanesulfonylchloride (89.4 g) (internal temperature: 39 to 50° C.), and stirred atthe same temperature for 20 minutes. To the reaction mixture weresuccessively added dropwise triethylamine (79 g) and methanesulfonylchloride (89.4 g) (internal temperature: 42 to 50° C.), and then stirredat the same temperature for 25 minutes. To the reaction mixture weresuccessively added dropwise additional triethylamine (39.5 g) andmethanesulfonyl chloride (44.7 g) (internal temperature: 42 to 47° C.),and stirred at 40° C. for 4 hours. To the reaction mixture was addeddropwise water (1500 mL), the mixture was stirred at 40° C. for 1 hour,then cooled to 25° C., and then stirred for 30 minutes. The precipitatedcrystals were collected by filtration, successively washed withacetonitrile/water (1:1, 300 mL) and water (750 mL), and dried to obtainthe title compound (235.1 g) as white crystals (yield: 87%, purity:99%).

MS: ESI-MS m/Z: 349 [M+H]⁻

¹H-NMR (CDCl₃): δ 1.54 (6H, s), 2.20 (1H, brs), 3.41 (6H, s), 6.85 (1H,d), 6.95 (1H, d), 6.96 (1H, s)

(2) Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide

The compound (300.0 g) obtained in the above step (1),4-fluorophenylboronic acid (210.8 g), 4-dimethylaminopyridine (21.0 g),tributylamine (127.7 g) and copper(II) acetate monohydrate (17.2 g) wereadded to dimethylsulfoxide (2250 mL), and the mixture was stirred at 20°C. for 25 hours under blowing air (150 mL/min) thereto. To the reactionmixture was added methanol (1500 mL), and then to the mixture was addeddropwise hydrochloric acid/water (179 g/2130 mL) at about 30° C. orlower. After the mixture was stirred for 1 hour, the precipitatedcrystals were successively washed with water (3000 mL) and methanol(1500 mL), and then dried to obtain the title compound (350.5 g) aswhite crystals (yield: 92%, purity: 94%).

MS: ESI-MS m/Z: 443 [M+H]⁻

¹H-NMR (CDCl₃): δ 1.63 (6H, s), 3.39 (6H, s), 6.40 (1H, d), 6.84 (1H,dd), 7.03 (1H, d), 7.20-7.25 (4H, m)

(3) Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

The compound (10 g) obtained in the above step (2) was dissolved indimethylsulfoxide (60 mL), and the solution was filtered to removeinsoluble materials. After the filtrate and the washings were combined,an aqueous solution of anhydrous potassium carbonate (9.4 g/10 mL) wasadded dropwise thereto at 30° C. or lower, and the mixture was stirredat the same temperature for 25 hours. To the reaction mixture was addeddropwise concentrated hydrochloric acid/water (4.7 g/90 mL) at 30° C. orlower, and the mixture was stirred for 30 minutes. The precipitatedcrystals were collected by filtration, and successively washed withwater (90 mL) and ethanol (20 mL) to obtain the title compound (9.1 g)as white crystals (Form B crystals). The crystals were suspended inethanol (100 mL), the suspension was heated under reflux for 2 hours,and then cooled to room temperature. The precipitated crystals werecollected by filtration, and dried under reduced pressure at 50° C. toobtain the title compound (7.1 g) as crystals (Form A crystals) (yield:86%, purity: 99%).

M.p.: 240° C.

MS: ESI-MS m/Z: 365 [M+H]⁻

¹H-NMR (DMSO-d₆): δ 1.51 (6H, s), 2.95 (3H, s), 6.25 (1H, d), 6.75 (1H,dd), 6.90 (1H, d), 7.35-7.41 (4H, m), 9.69 (1H, brs)

Example 2 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

To a suspension ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide(1 g) in acetone (3 mL) was added dropwise an aqueous sodium hydroxidesolution (0.18 g/3 mL) at 25° C., and the mixture was stirred at thesame temperature for 90 minutes. To the reaction mixture was addeddropwise concentrated hydrochloric acid/acetone/water (0.24 g/0.5mL/0.35 mL) at 25° C., and the mixture was stirred for 2 hours. Theprecipitated crystals were collected by filtration, washed with asolution of acetone/water (1:1. 6 mL), and then dried under reducedpressure at 50° C. to obtain the title compound (0.79 g) as Form Acrystals (yield: 95%, purity: 100%).

M.p.: 240° C.

Example 3 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

To a suspension ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide(1 g) in dimethylsulfoxide (3 mL) was added dropwise an aqueous sodiumhydroxide solution (0.18 g/3 mL) at 25° C., then dimethylsulfoxide/water(1:1. 2 mL) was added thereto, and the mixture was stirred overnight atthe same temperature. To the reaction mixture was added dropwiseconcentrated hydrochloric acid/dimethylsulfoxide/water (0.24 g/0.5mL/0.35 mL) at 25° C., and the mixture was stirred for 5 hours. Theprecipitated crystals were collected by filtration, successively washedwith a solution of dimethylsulfoxide/water (1:1.6 mL) and water (10 mL),and then dried under reduced pressure at 50° C. to obtain the titlecompound (0.81 g) as Form A crystals (yield: 98%, purity: 100%).

M.p.: 240° C.

Example 4 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

To a suspension ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide(1 g) in ethanol (3 mL) was added dropwise an aqueous sodium hydroxidesolution (0.18 g/3 mL) at 25° C., then ethanol/water (1:1.2 mL) wasadded thereto, and the mixture was stirred overnight at the sametemperature. To the reaction mixture was added dropwise concentratedhydrochloric acid/ethanol/water (0.24 g/0.5 mL/0.35 mL) at 25° C., andthe mixture was stirred for 1 hour. The precipitated crystals werecollected by filtration, washed with a solution of ethanol/water (1:1. 6mL), and then dried under reduced pressure at 50° C. to obtain the titlecompound (0.80 g) as Form B crystals (yield: 98%, purity: 95%).

Example 5 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

To a suspension ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide(1 g) in isopropanol (3 mL) was added dropwise an aqueous sodiumhydroxide solution (0.18 g/3 mL) at 25° C., then isopropanol/water(1:1.2 mL) was added thereto, and the mixture was stirred overnight atthe same temperature. To the reaction mixture was added dropwiseconcentrated hydrochloric acid/isopropanol/water (0.24 g/0.5 mL/0.35 mL)at 25° C., and the mixture was stirred for 1 hour. The precipitatedcrystals were collected by filtration, washed with a solution ofisopropanol/water (1:1. 6 mL), and then dried under reduced pressure at50° C. to obtain the title compound (0.78 g) as Form D crystals (yield:94%, purity: 99%).

Example 6 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide

N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide(200 g), tris(4-fluorophenyl)boroxine (140.5 g), 4-dimethylaminopyridine(14.0 g), tributylamine (85.1 g) and copper(II) acetate monohydrate(11.5 g) were added to dimethylsulfoxide (1500 mL), and the mixture wasstirred at 20° C. for 72 hours under blowing air (850 mL/min) dehydratedwith silica gel thereto. To the reaction mixture was added dropwise anaqueous hydrochloric acid solution (concentrated hydrochloric acid(119.7 g)/water (1422 mL)) at 30° C. or lower, then methanol (1000 mL)was added thereto, and the mixture was stirred at 20° C. for 2 hours.The precipitated crystals were collected by filtration, successivelywashed with water (2000 mL) and methanol (1000 mL), and then suspendedin methanol (2000 mL). The suspension was heated under reflux for 1.5hours, then cooled to 20° C., and stirred at the same temperature for 30minutes. The precipitated crystals were collected by filtration, washedwith methanol (1000 mL), and then dried to obtain the title compound(226.2 g) (yield: 89%, purity: 99%).

Example 7 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide

N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide(7.50 g), 4-fluorophenylboronic acid (5.27 g), 4-dimethylaminopyridine(0.53 g), tributylamine (3.20 g) and copper(II) acetate monohydrate(0.43 g) were added to dimethylsulfoxide (56 mL), and the mixture wasstirred at 20° C. for 26 hours under blowing air (7 to 10 mL/min)thereto. The reaction mixture was added dropwise to a mixed solution ofdimethylsulfoxide/concentrated hydrochloric acid/water (19 mL/4.5 g/34mL) at about 15° C., and washed with dimethylsulfoxide (7.5 mL). Themixture was stirred at 10° C. for 3 hours, then the precipitatedcrystals were successively washed with dimethylsulfoxide/water (12 mL/3mL) and water (75 mL), and then dried to obtain the title compound (9.09g) as white crystals (yield: 95%, purity: 92%).

Example 8

N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide(40.0 g), 4-fluorophenylboronic acid (28.1 g), 1-methylimidazole (0.9g), tributylamine (27.3 mL) and copper(II) acetate (2.1 g) were added todimethylsulfoxide (300 mL), and the mixture was stirred at 20° C. for 34hours under nitrogen flow (120 mL/min) and blowing air (40 mL/min)thereto. The reaction mixture was added dropwise to a mixed solution ofdimethylsulfoxide/concentrated hydrochloric acid/water (110.0 g/24.0g/180.0 g) at about 15° C., and washed with dimethylsulfoxide (44.0 g).The mixture was stirred at 10° C. for 2 hours, then the precipitatedcrystals were successively washed with dimethylsulfoxide/water (70.4g/16.0 g) and water (400.0 g), and then dried to obtain the titlecompound (47.8 g) as white crystals (yield: 94%, purity: 94%).

Example 9

N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide(40.0 g), 4-fluorophenylboronic acid (28.1 g), tributylamine (21.8 mL)and copper(II) acetate (12.5 g) were added to dimethylsulfoxide (300mL), and the mixture was stirred at 40° C. for 71 hours under nitrogenflow (120 mL/min) and blowing air (40 mL/min) thereto. The reactionmixture was added dropwise to a mixed solution ofdimethylsulfoxide/concentrated hydrochloric acid/water (110.0 g/24.0g/180.0 g) at about 15° C., and washed with dimethylsulfoxide (44.0 g).After the mixture was stirred at 10° C. for 2 hours, the precipitatedcrystals were successively washed with dimethylsulfoxide/water (70.4g/16.0 g) and water (400.0 g), and then dried to obtain the titlecompound (47.6 g) as white crystals (yield: 94%, purity: 91%).

Example 10 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide

N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide(8.5 g) was dissolved in dimethylsulfoxide (51 mL), a solution ofpotassium carbonate/water (7.98 g/8.5 mL) was added dropwise thereto at25° C., and the mixture was stirred at the same temperature for 23hours. To the reaction mixture was added dropwise concentratedhydrochloric acid/water (4.0 g/76.5 mL) at 30° C. or lower, then cooledto 20° C., and the mixture was stirred for 90 minutes. The precipitatedcrystals were collected by filtration, washed with water (76.5 mL), andthen dried to obtain the title compound (6.40 g) as white crystals (FormB crystals). Subsequently, said crystals (6 g) were added todimethylsulfoxide (21 mL), dissolved at about 50° C., then activatedcarbon (120 mg) and dimethylsulfoxide (3 mL) were added thereto, andstirred for 1 hour. After the mixture was filtered, to the filtrate atabout 50° C. was added dropwise purified water (9 mL), and then stirredat the same temperature for 30 minutes. The mixture was cooled to 20°C., stirred for 1 hour, then the precipitated crystals were collected byfiltration, and successively washed with purified water (54 mL) andethanol (12 mL). The obtained crystals (6.57 g) were suspended inethanol (30 mL), the suspension was heated under reflux for 2 hours,then cooled to 20° C., and stirred for 1 hour. The precipitated crystalswere collected by filtration, and dried under reduced pressure at 50° C.to obtain the title compound (5.48 g) as crystals (Form A crystals)(yield: 83%, purity: 100%).

Experimental Example 1

X-ray crystallographic analysis under the following conditions wascarried out on each of the crystals (Form A crystal, Form B crystal andForm D crystal) of the target compound obtained in the above eachEXAMPLE, and the crystal (Form C crystal) obtained by the experiment forscreening crystal forms. As a result of the analysis, it was confirmedthat the Form A crystal (i.e., crystal obtained in EXAMPLES 1, 2 and 3),the Form B crystal (i.e., crystal obtained in EXAMPLE 4), and the Form Ccrystal were novel crystal forms each having a clearly different XRDpattern from the crystal form of the compound [A] disclosed in PatentLiterature 1 (Example 9). Meanwhile, by the analyses such as X-raycrystallographic diffraction and melting point, it was confirmed thatthe Form D crystal (i.e., crystal obtained in EXAMPLE 5) was the same asthe crystal form of the compound [A] (i.e., compound obtained inREFERENCE EXAMPLE 2) prepared according to the method disclosed inPatent Literature 1 (Example 9). The XRD diffraction pattern of eachcrystal form obtained in the EXAMPLES of the present specification isshown in the following FIG. 1 to FIG. 4. Also, the diffraction angle(2θ) values of the diffraction peaks observed in each crystal form areshown in Table 1 to Table 4.

Device name: DISCOVER with GADDS CS (made by BRUKER CORPORATION)

X-ray source: CuKα

Tube voltage: 40 kV

Tube current: 40 mA

Measurement range (2θ): 5 to 37°

Detector: Multiwire two-dimensional PSPC

FIG. 1 shows the X-ray powder diffraction pattern of the Form A crystalof the compound [A].

FIG. 2 shows the X-ray powder diffraction pattern of the Form B crystalof the compound [A].

FIG. 3 shows the X-ray powder diffraction pattern of the Form C crystalof the compound [A].

FIG. 4 shows the X-ray powder diffraction pattern of the Form D crystalof the compound [A].

Table 1 shows the diffraction angles (2θ) of the Form A crystal of thecompound [A].

Table 2 shows the diffraction angles (2θ) of the Form B crystal of thecompound [A].

Table 3 shows the diffraction angles (2θ) of the Form C crystal of thecompound [A].

Table 4 shows the diffraction angles (2θ) of the Form D crystal of thecompound [A].

TABLE 1 Peak No. 2θ (°) 1 6.4 2 7.4 3 8.3 4 9.7 5 10.2 6 11.2 7 13.0 813.6 9 14.2 10 16.0 11 16.4 12 17.3 13 18.1 14 20.2 15 20.9 16 21.3 1722.4 18 23.7 19 25.1 20 25.7 21 27.3 22 28.1 23 28.8 24 29.5 25 30.3 2630.8 27 31.4 28 33.2 29 33.9 30 34.5 31 35.2 32 36.6

TABLE 2 Peak No. 2θ (°) 1 7.5 2 10.2 3 10.8 4 12.0 5 12.7 6 14.8 7 15.98 16.9 9 18.3 10 19.3 11 20.0 12 21.5 13 22.3 14 23.2 15 24.2 16 25.6 1726.9 18 27.8 19 29.1 20 30.1 21 30.9 22 31.6 23 32.6 24 33.6 25 34.3 2636.1

TABLE 3 Peak No. 2θ (°) 1 11.3 2 12.1 3 13.0 4 14.3 5 15.7 6 17.0 7 17.88 19.3 9 21.2 10 22.4 11 23.4 12 24.3 13 25.1 14 25.9 15 26.4 16 27.5 1728.6 18 29.6 19 31.1 20 31.6 21 32.2 22 33.6 23 34.9 24 36.0 25 36.4

TABLE 4 Peak No. 2θ (°) 1 6.0 2 11.9 3 12.7 4 13.6 5 14.4 6 15.7 7 17.08 17.6 9 19.0 10 20.4 11 21.5 12 21.8 13 22.5 14 23.3 15 24.1 16 24.8 1726.5 18 28.1 19 28.7 20 30.2 21 31.2 22 31.4 23 32.1 24 33.7 25 35.4 2636.1

The Form A crystal (or Form B crystal) and the Form D crystal areclearly different from each other in that while the former crystal hasat least one diffraction peak at 6.7° to 11.0° as the diffraction angle(2θ±0.2°), the latter crystal does not have any diffraction peak at 6.7°to 11.0° as the diffraction angle (2θ±0.2°) in their XRD patterns (FIG.1, FIG. 2, FIG. 4, Table 1, Table 2 and Table 4). This fact teaches thatthe Form A crystal and the Form D crystal have different crystalstructures from each other. Meanwhile, it was confirmed that the Form Dcrystal has the same crystal form as the crystal of the compound [A]prepared according to the method disclosed in Patent Literature 1(WO2007/089034, Example 9) (see REFERENCE EXAMPLE 2 described below).

Reference Example 1 (1) Preparation of2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H)-one

To a solution of 2-amino-5-nitrophenol (200 g) in dimethylsulfoxide(1000 mL) was added anhydrous potassium carbonate (269 g) under stirringat 30° C. or lower, then to the mixture was added ethyl2-bromo-2-methylpropionate (278.4 g) at 30° C. or lower, and the mixturewas stirred at 26° C. for 24 hours. To the reaction mixture was addedwater (2000 mL) at 40° C. or lower, and then stirred at room temperaturefor 3 hours. The reaction product was collected by filtration, andsuccessively washed with dimethylsulfoxide/water (2:1, 800 mL) and water(3200 mL) to obtain the title compound (348.6 g) as a yellow solid (wetmaterial) (yield: 121%, purity: 96%).

MS: ESI-MS m/Z: 223 [M+H]⁻

¹H-NMR (CDCl₃): δ 1.59 (6H, s), 6.95 (1H, d), 7.87 (1H, d), 7.92 (1H,dd), 9.38 (1H, brs)

(2) Preparation of 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one

A mixture of the compound (wet material: 384.6 g) obtained in the abovestep (1), methanol (2880 mL), and 20% palladium hydroxide carbon (13.8g) was stirred under hydrogen pressure (0.1 MPa) at 40° C. untilhydrogen absorption terminated (about 4 hours). The reaction mixture wasfiltered, and the unfiltered residue was washed with methanol (300 mL).The filtrate and the washings were combined, then concentrated underreduced pressure at 50° C. or lower, to the residue were added methanol(288 mL) and water (1440 mL), and the mixture was stirred at 50° C. forabout 1 hour. The mixture was cooled to 25° C., then stirred for 30minutes, the precipitated crystals were collected by filtration, washedwith water (1440 mL), and then dried to obtain the title compound(163.94 g) as red-brown crystals (yield: 66%, purity: 100%).

MS: ESI-MS m/Z: 193 [M+H]⁻

¹H-NMR (CDCl₃): δ 1.51 (6H, s), 3.56 (2H, brs), 6.29 (1H, dd), 6.32,6.33 (1H, m), 6.59 (1H, d), 8.34 (1H, brs)

Reference Example 2 Preparation ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide(Form D crystal)

The compound [A] was prepared by the following steps according to themethod disclosed in Patent Literature 1.

To a solution of7-amino-4-(4-fluorophenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one(11.0 g) in chloroform (200 mL) were added dropwise methanesulfonylchloride (4.46 mL) and pyridine (6.21 mL) under ice cooling, and thenthe mixture was stirred at room temperature for 17 hours. To thereaction mixture was poured an aqueous saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. Theorganic layer was successively washed with water, 10% hydrochloric acidand a saturated saline, then dried over sodium sulfate, and concentratedunder reduced pressure. The obtained residue was suspended in ethylacetate, and then the precipitated materials were collected byfiltration, and washed with ethyl acetate to obtain the title compound(10.2 g) as a pale pink powder.

APCI-MS m/z: 365 [M+H]⁻

M.p.: 233° C.

¹H-NMR (CDCl₃): δ 1.60 (6H, s), 3.01 (3H, s), 6.32 (1H, d), 6.44 (1H,brs), 6.69 (1H, dd), 6.95 (1H, d), 7.20-7.22 (4H, m)

Industrial Applicability

By using the method of the present invention, the 1,4-benzoxazinecompound [A] useful as a medicine can be prepared in a high yield.Furthermore, the method of the present invention can use an intermediatehaving lower mutagenicity, and thus is also characterized by lowersafety and health risks and can be an industrially advantageous methodfor producing the 1,4-benzoxazine compound [A].

Also, the crystals (Form A crystal etc.) of the compound [A] of thepresent invention are useful as a preventive or therapeutic agent fordiseases such as hypertension or a renal disease (diabetic nephropathyetc.).

1. A method for producing a 1,4-benzoxazine compound of the followingformula [A]:

which comprises the following steps of: (step a) reacting a compound ofthe following formula [a]:

with methanesulfonyl halide in the presence of a base to produce acompound of the following formula [b]:

wherein Ms is a methanesulfonyl group, (step b) reacting said compound[b] with a boronic acid compound of the following formula [d]:

wherein R and R′ are the same or different and each of them is ahydrogen atom or an alkyl group, or both of them combine together toform an alkylene group, or an equivalent thereof, in the presence of acopper catalyst, in the presence or absence of a base, and in thepresence or absence of a ligand to produce a compound of the followingformula [c]:

wherein the symbol is the same as defined above, and (step c) convertingthe substituent at 7-position (dimesylamino group) in said compound [c]into a monomesylamino group to produce the compound of the above formula[A].
 2. The method according to claim 1, wherein the methanesulfonylhalide is methanesulfonyl chloride.
 3. The method according to claim 1,wherein the compound [d] is a compound of the following formula:

or an equivalent thereof.
 4. The method according to claim 1,characterized in that the step a is carried out in a solvent selectedfrom the group consisting of acetonitrile, methyl ethyl ketone, ethylacetate, tetrahydrofuran and acetone, and in the presence of a baseselected from triethylamine, tetramethylethylenediamine and1,8-diazabicyclo[5.4.0]undec-7-ene, the step b is carried out in asolvent selected from dimethylsulfoxide and N,N-dimethylacetamide, inthe presence of a copper catalyst selected from the group consisting ofcopper acetate, copper halide, copper nitrate and a copper salt oftrifluoromethanesulfonic acid, in the presence or absence of one or morebases selected from triethylamine, diisopropylethylamine, tributylamine,tripropylamine, trioctylamine, dimethylbenzylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, N-ethylmorpholine,N-methylmorpholine, sodium hydrogen carbonate and an aqueous ammonia, inthe presence or absence of one or more ligands selected fromdimethylaminopyridine, 2-aminopyridine, 4-methylpyridine,2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine, N-methylimidazole,N-butylimidazole and pyrazine, and under oxygen supply to the reactionsystem, and the step c is carried out in a solvent selected fromethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone anddimethylsulfoxide or a mixture of said solvent and water, and in thepresence of a base selected from potassium carbonate and sodiumhydroxide.
 5. A method for producing a compound of the following formula[A]:

which comprises the step of converting the substituent at 7-position(dimesylamino group) in a compound of the following formula [c]:

wherein Ms is a methanesulfonyl group, into a monomesylamino group. 6.The method according to claim 5, characterized in that the conversion ofthe substituent at 7-position (dimesylamino group) into themonomesylamino group is carried out in a solvent selected from ethanol,isopropanol, n-propanol, acetone, methyl ethyl ketone anddimethylsulfoxide or a mixture of said solvent and water, and in thepresence of a base selected from potassium carbonate and sodiumhydroxide.
 7. A crystal (Form A crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide,which has at least one diffraction peak at 6.7° to 11.0°, and hasdiffraction peaks at 18.1° and 23.7° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction.
 8. The crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to claim 7, which has an additional diffraction peak at 10.2°as the diffraction angle (2θ±0.2°).
 9. A crystal (Form B crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide,which has at least one diffraction peak at 6.7° to 11.0°, and hasdiffraction peaks at 14.8° and 18.3° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction.
 10. The crystal ofN[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to claim 9, which has additional diffraction peaks at 10.8°and 23.2° as the diffraction angle (2θ±0.2°).
 11. A crystal (Form Ccrystal) of a dimethylsulfoxide monosolvate ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide, which hasdiffraction peaks at 19.3° and 29.6° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction.
 12. The crystal of thedimethylsulfoxide monosolvate ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to claim 11, which has an additional diffraction peak at 11.3°as the diffraction angle (2θ±0.2°).
 13. A pharmaceutical compositioncomprising the crystal ofN[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideor a dimethylsulfoxide monosolvate thereof according to claim 7 and apharmacologically acceptable carrier.
 14. The pharmaceutical compositionaccording to claim 13, which is a preventive or therapeutic agent forvarious diseases or disease states caused by enhanced MR activity and/orelevated aldosterone level.
 15. The pharmaceutical composition accordingto claim 13, which is a preventive or therapeutic agent forhypertension, heart failure, myocardial infarction, angina, cardiachypertrophy, myocarditis, myocardial/vascular fibrosis, baroreceptordysfunction, volume overload or arrhythmia.
 16. The pharmaceuticalcomposition according to claim 13, which is a preventive or therapeuticagent for primary/secondary aldosteronism, Addison's disease, Cushing'ssyndrome or Bartter's syndrome.
 17. The pharmaceutical compositionaccording to claim 13, which is a preventive or therapeutic agent for arenal disease.
 18. The pharmaceutical composition according to claim 17,wherein the renal disease is diabetic nephropathy.
 19. A method forproducing a Form A crystal ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving at least one diffraction peak at 6.7° to 11.0°, and havingdiffraction peaks at 18.1° and 23.7° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction, which comprises the step of heating acrystal (Form D crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving no diffraction peak at 6.7° to 11.0°, but having diffractionpeaks at 6.0°, 11.9°, 17.0°, 17.6° and 19.0° as the diffraction angle(2θ±0.2°), or a crystal (Form B crystal) ofN-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamidehaving at least one diffraction peak at 6.7° to 11.0°, and havingdiffraction peaks at 14.8° and 18.3° as the diffraction angle (2θ±0.2°)in the X-ray powder diffraction in a liquid medium or in the absence ofa medium.
 20. The method for producing the Form A crystal ofN[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamideaccording to claim 19, characterized by heating the Form B crystal inethanol as the liquid medium at 75° C. to 85° C.